The long term objective of this application is to understand the roles that pre-amyloid oligomers (PAO) may play in human heart failure. We noted that cardiomyocytes from diseased hearts contain a protein that reacts to antibodies able to detect a toxic protein(s), PAO, which is normally associated with the amyloid-based neurodegenerative diseases. Subsequently, we found that PAO is present in cardiomyocytes derived from a limited number of human heart failure patients of different etiologies, implying that it may be an important mediator of cardiovascular disease. We think that the 1B crystallin mutant mouse, which also accumulates PAO in the cardiomyocytes, is a uniquely useful and relevant system that models a heretofore understudied phenomenon, accumulation of PAO in the cardiomyocytes of both adult and pediatric heart failure patients. The goals, therefore, are to understand the pathogenic pathway that results in PAO accumulation, determine its toxicity in cardiomyocytes and define potential therapeutic targets or modalities for the resultant dilated cardiomyopathy and heart failure that occurs as a result of CryABR120G expression. Aim 1 will test the hypothesis that cardiomyocyte accumulation of PAO is widespread in the human heart failure population, across age groups and disease types. Aim 2 will use inducible, cardiomyocyte-specific CryABR120G (a mutant protein causative for human muscle disease), expression to test the hypothesis that PAO-mediated heart failure can be reversed. Aim 3 will express anti-apoptotic factors in CryABR120G cardiomyopathic hearts to determine if prevention of programmed cell death can, in the face of continuous CryABR120G expression, prevent heart failure or even reverse existing disease. We hypothesize that despite the occurrence of cardiomyocyte apoptosis in CryABR120G hearts, programmed cell death is peripheral and collateral to the primary etiology that transits the hearts toward failure in this model. These studies have the potential of establishing broad linkages between the neurodegenerative and cardiovascular diseases and identifying new targets for interfering with processes that occur in a broad range of cardiovascular disease. We have found that the heart contains a protein that is normally associated with neurodegenerative diseases. This toxic protein is only found in diseased hearts and our experiments will examine exactly when and where the protein accumulates and how it causes cardiovascular disease.